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Department of Neurosurgery

Diffusely Infiltrating Gliomas with Non- Significant Contrast-Enhancement : Is 1 H-Magnetic Resonance Spectroscopy Chemical Shift Imaging a Clinically Reliable Technique for Detection of Malignant Intratumoral Areas. Department of Neurosurgery. Georg Widhalm. Inhomogeneity of Gliomas .

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Department of Neurosurgery

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  1. DiffuselyInfiltratingGliomaswithNon-SignificantContrast-Enhancement: Is 1H-Magnetic ResonanceSpectroscopy Chemical Shift Imaging a ClinicallyReliableTechniqueforDetectionofMalignantIntratumoral Areas Department of Neurosurgery Georg Widhalm

  2. Inhomogeneity of Gliomas • Diffusely infiltrating gliomas (DIG) are frequently histologically heterogeneous with development of malignant intratumoral areas (=anaplastic foci) • Surgery: Problem of target definition (=representative tumor sample) for intraoperative tissue sampling • Neuropathology: Danger of histopathological undergrading • Adjuvant treatment: Accurate histological dignosis is essential for allocation of the patients to the adequate treatment • Optimization of intraoperative tumor tissue sampling is needed Paulus et al; Cancer; 1989

  3. Current Methods for Detection of Anaplastic FociMRI • Routinely, anaplastic foci are identified by contrast-enhancement (CE) on MRI sampled intraoperatively using neuronavigational guidance • However, a considerable number of DIG WHO grade II and III lack significant CE • Therefore, CEis often not a reliable parameter for identification of anaplastic foci

  4. DIG with non-significant CE • Up to 55% of cases with non-significant CE arealready WHO grade III gliomas • DIG with non-significant CE constitute a special challenge to the neuroradiologist and neurosurgeon in selecting a representative intraoperative tumor ?

  5. Current Methods for Detection of Anaplastic FociPET • Positron emission tomography (PET) is a powerful method for detection of anaplastic foci in DIG • Frequently PET with amino-acid tracers (e.g. ¹¹C-methionine-PET (MET-PET) or 18F- fluoroethyl-L-tyrosine-PET (FET-PET) is used • Neuronavigation based on PET data co-registered with anatomic images is frequently used for intraoperative detection of malignant areas • However, PET is available only in highly specialized neurooncologicalcenters

  6. New Methods for Detection of Anaplastic Foci1H-MR-Spectroscopy (MRS) In-plane multivoxel matrix (1 cm slice- thickness= 2-D CSI) Creation of color coded maps of metabolic ratios (Cho/NAA or Cho/Cr): red color code visualizes the tumor area with the highest CSI ratio

  7. Inegrationof CSI intoneuronavigation MR T2 (15 slices) MR T1 CE (85 slices) co-planar acquisition Step 1Image Fusion Step 2 Copy registration file = Step 3Loadinto Navigation System MR T1 CE + CSI on Navigation Screen CSI sandwich(5 empty slices 5 identical CSI slices 5 empty slices)

  8. Presentstudy • We investigated the clinical usability of CSI for detection of malignant areas in diffusely infiltrating gliomas in comparison to standard MET-PET • 32 consecutive patients with diffusely infiltrating gliomas • July 2007 and November 2009 • MRI, 2-D CSI (3T MR scanner) and MET-PET in all patients • CSI (Cho/Cr and Cho/NAA): ratio of > 1.0 was considered as pathologic • MET-PET tumor/normal (T/N) brain ratio : • normal (T/N: <1.15) • unspecific tracer uptake (T/N: 1.15 and <1.5) • pathologic (T/N: > 1.5 ) • Histologic criteria of anaplasiaas well as cell proliferation rate was assessed in • tumor samples inside and outside of maximum pathologic PET and/or CSI ratios Widhalm et al; JNNP 2010

  9. Study Design • Previous studies have shown that MET-PETmax (maximal tracer uptake) represents areas with highest malignancy within diffusely infiltrating gliomas • Therefore we used in our study MET-PETmaxas reference for topographic correlation with CSImax(maximal pathologic CSI ratio) Sadeghi et al; AJNR; 2007

  10. Study Design • After co-registration of MRI with CSI and MET-PET the topographic overlap of CSImaxand PETmax was analyzed: • overlap > 50% • overlap < 50% • distant (no overlap) PETmax CSImax PETmax+ CSImax

  11. Results MET-PET: 21/32 pathologic CSI: ratios abnormal in all patients

  12. TopographicPETmax/CSImaxCorrelation(n=21/32 pts) overlap > 50%: n= 18/21 pts PETmax CSImax PETmax+CSImax overlap < 50%: n= 3/21 pts PETmax CSImax PETmax+CSImax

  13. Topographic Cho/Crmaxand Cho/NAAmaxCorrelation(n=32 pts) overlap > 50%: n= 24/32 pts Cho/NAAmax Cho/Crmax Cho/NAAmax+Cho/Crmax overlap < 50%: n= 8/32 pts (6 central Cho/NAA, peripheral Cho/Cr) Cho/NAAmax Cho/Crmax Cho/NAAmax+Cho/Crmax

  14. Results- Neuropathology

  15. CSImax, PET not pathologic(n=11/32; 7 WHO II, 4 WHO III tumors) mixedoligoastrocytoma WHO III MR T1 CE CSImax MET-PET negative insideCSImax outside CSImax HE MIB-1: > 42% HE MIB-1: < 9%

  16. Limitations of Methods for iOP Identifikation of Anaplastic Foci Navigation withpreoperativeimaging: • MRI+CE • Metabolicimaging (PET, CSI) Cave: Brain shift! Intraoperativeimaging: • iOP MRI • 5-ALA ?

  17. 5-ALA • 5-Aminolevulinic acid (5-ALA) leads after oral application to intracellular accumulation of strongly fluorescing protophorphyrin IX in malignant glioma tissue • Fluorescence can be visualised by a modified neurosurgical microscope with violet-blue excitation light • Intraoperativeidentification of (residual)-malignant glioma tissue

  18. 5-ALA in Gliomaswith non-significant CE-5-ALA is a Promising Marker for Detection of Anaplastic Foci in Diffusely Infiltrating Gliomas with Non-Significant CE • 17 gliomas with non-significant CE • 3 T MRI +CM + MET-PET • 5-ALA (20mg/kg KG ) 3 hours before anesthesia • iOP: microscope was switched from conventional white light to violet-blue excitation light repeatedly • 5-ALA fluorescence inside/outside PETmax: yes (ALA+) or no (ALA-) was noted • Topographic correlation with maximum PET tracer uptake (PETmax) Widhalm et al; Cancer 2010

  19. 5-ALA Fluorescence Focal 5-ALA fluorescence correlated topographically with PETmax in all patients

  20. MIB-1: ALA neg v/s ALA pos in the same tumor

  21. Outside PETmax ALA - low grade tumor MIB-1: 5% PET max ALA + anaplastic focus MIB-1: 14.4% Diagnosis: Anaplastic Astrocytoma WHO °III

  22. Conclusions Detection of Anaplastic Foci in Gliomas with non-significant CE • CSI is a clinically reliable technique for detection of malignant intratumoral areas within DIG with non-significant CE • Intraoperative use of CSI by multimodal neuronavigation may increase the reliability of detection of malignant areas in glioma surgery and therefore optimize allocation of patients to adjuvant treatments • 5-ALA is an additional promising marker in gliomas with non-significant CE for visualization of anaplastic foci that has the advantage of being unaffected from intraoperative brain-shift

  23. Team approach • NeurosurgeryE. KnospS. WolfsbergerG. Minchev A. Mert • Radiology / High field-MRID. PrayerM. Krssak G. KasprianJ. FurtnerS. Trattnig E. Springer • Institute of NeurologyJ. HainfellnerA. Wöhrer • Neurology/Nuclear MedicineS. AsenbaumT. Traub-Weidinger • Internal Medicine IC. MarosiM. Preusser 5-ALA training course Nov. 2009 Vienna Georg.widhalm@meduniwien.ac.at

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